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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
  • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
  • A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/10—Antioedematous agents; Diuretics

Definitions

• the present invention relates to a teverelix-TFA composition.
• Teverelix is a synthetic gonadotropin-releasing hormone antagonists (GnRH antagonists) that compete with the endogenous neurohormone GnRH (otherwise known as luteinizing hormone releasing hormone, LHRH) for binding to its receptors in the anterior pituitary gland.
• GnRH antagonists synthetic gonadotropin-releasing hormone antagonists
• LHRH luteinizing hormone releasing hormone
• FSH and LH are involved in normal reproductive function.
• FSH stimulates the growth of immature Graafian follicles to maturation, whereas changes in LH levels control ovulation.
• FSH plays an important role in spermatogenesis and LH stimulates production of testosterone in the testes.
• teverelix is suitable for treatment of hormone- dependent conditions such as benign prostatic hypertrophy, hormone-dependent prostate cancer, endometriosis and uterine myomas .
• teverelix (Ac-D-Nal-D-pClPhe-D-Pal-Ser-Tyr-D-Hci-Leu- Lys ( iPr) -Pro-D-Ala-NH 2) is a hydrophobic peptide it has a tendency of forming gels in the presence of many counter-ions. This problem has been solved in WO 2003/022243 which discloses that the formation of a gel may be prevented by contacting the teverelix peptide with a counter-ion, e.g.
• TSA trifluoroacetate
• a ratio of teverelix to the counter-ion trifluoroacetate of at least 1:1.6 is essential in order to ensure the desired microcrystalline suspension is obtained, otherwise a gel will be formed.
• the inventors of the present invention has found that such molar ratios will result in both undesirable gel-formation and in suspensions which are not homogenous. This is a problem, not only because such suspensions will be difficult to inject, but also because the bioavailability of the teverelix peptide is compromised since the gel interferes with the desired sustained action of said peptide.
• teverelix-TFA composition having a molar ratio of teverelix to trifluoroacetate of at least 1:2.2.
• molar ratio of teverelix to trifluoroacetate refers to the molar relationship between teverelix and trifluoroacetate , where the first number of the molar ratio is the mol content of teverelix in the composition and the second number refers to the mol content of TFA in the composition.
• a molar ratio of 1:2.2 means that for each mol teverelix in the composition, said composition comprises 2.2 mol TFA
• a molar ratio of at least 1:2.2 means that for each mole teverelix in the composition, the composition comprises at least 2.2.
• mol trifluoroacetate (TFA) mol trifluoroacetate
• the inventors of the present invention have found that when the molar ratio of teverelix to trifluoroacetate is at least 1:2.2 composition will comprise both soluble and insoluble teverelix, thereby providing a unique bioavailablity of teverelix.
• teverelix For the teverelix to be absorbed in the body, said ingredient must be present in the form of solution at the site of absorption.
• Various techniques are used for the enhancement of the solubility of poorly soluble drugs, such as teverelix, however the inventors have found that crystal engineering, in which the teverelix and trifluoroacetate provides an organisation of the teverelix peptide and its counter-ion in a crystalline structure provides an effective sustained release of teverelix, having improve physicochemical properties (e.g., solubility and stability), and improve efficacy (e.g., bioavailability) .
• physicochemical properties e.g., solubility and stability
• efficacy e.g., bioavailability
• the soluble teverelix is in the form of an aqueous solution, and in some situations a gel.
• the presence of a gel will inhibit any freely aqueous teverelix and therefore prevent, or at least reduce, immediate release.
• the insoluble teverelix is in the form of microcrystals. Said microcrystals will prevent gel formation, therefore "unlocking" the aqueous teverelix.
• the TFA in the composition according to the invention will be absorbed by the body, lowering the ratio, so the microcrystals subsequently turn in to gel, which forms the slow release depot.
• the non-gel-soluble teverelix is immediately available, providing an almost immediate onset of action, and the gel-soluble and insoluble teverelix (microcrystals) will assist in providing a sustained release of teverelix.
• the composition according to the invention provides a soluble-insoluble transition at the administration site, and accordingly a sustained release of teverelix.
• the composition according to the invention has both an immediate onset of action leading to a fast suppression of the gonadotropins, but also a sustain release of antagonist thereby ensuring that the subject maintains a therapeutically effective concentration in the blood plasma.
• This will not only provide a more reliable composition for the treatment of gonadotropin relates diseases and conditions, but also improve patient compliances as fewer administrations (e.g. injections) are required .
• the molar ratio of teverelix to trifluoroacetate is preferably at least 1:2.2, i.e. for each mole of teverelix, the composition comprises at least 2.2. mol trifluoroacetate (TFA) , and even more preferred at least 1:2.4 as this will provide an aqueous pharmaceutical formulation that may be used directly, i.e. the formulation is ready-to-use .
• TFA trifluoroacetate
• impurities may influence quality, safety and efficacy of the teverelix composition/formulation, thereby potentially causing serious health hazards.
• the inventors of the present invention has found that the level of impurities are kept at an acceptable level, when the molar ratio of teverelix to TFA is at or below 1:2.8, i.e. when the molar content of TFA is at or below 2.8 per mol teverelix.
• the optimal molar ratio in the composition according to the invention is preferably between 1:2.2 (or 1:2.4) and 1:2.8.
• the composition according to the invention is especially suitable for treating a condition such as prostate cancer through a suppression of gonadotropins such as testosterone and dihydrotestosterone (DHT) . Since such a composition both will have an immediate onset of action leading to a profound suppression of testosterone, and a sustain release of antagonist thereby ensuring that the subject maintains chemically castrated, the composition is both valuable in the treatment of patients with prostate cancer where fast control of disease is needed and for patients where only sustained release is relevant.
• gonadotropins such as testosterone and dihydrotestosterone (DHT)
• composition according to the invention may however equally well be used to at least partially ameliorating other diseases or condition related to the release of a gonadotropin hormone.
• Said disease or condition may be benign prostatic hyperplasia; acute urinary retention; endometriosis; a cancer such as prostate, breast, or cervical cancer; chemical castration; a hormone imbalance; an androgen-sensitive condition; an estrogen sensitive condition; or a combination thereof.
• the present invention also relates to an aqueous pharmaceutical formulation, preferably a milky, microcrystalline homogeneous aqueous suspension, consisting of or comprising the teverelix- TFA composition according to the invention with a molar ratio of teverelix to trifluoroacetate of at least 1:2.2, preferably at least about 1:2.4.
• a molar ratio of teverelix to trifluoroacetate is below 1:2.8, i.e. per 1 mol teverelix the formulation contains 2.8 mol TFA, or less.
• the aqueous pharmaceutical formulation may contain an isotonic agent, such as mannitol and/or a pharmaceutically acceptable excipient.
• the teverelix-TFA composition is provided as a unit dosage having a molar ratio of teverelix to TFA which is at least 1:2.2 and even more preferred about 1:2.4 thereby ensuring that the provided suspension contains substantially no gel, or at least so small concentrations of gel that the suspension can be used for injections.
• a package e.g. a syringe or vial, filled with a unit dosage of the teverelix-TFA composition.
• unit dosage is the amount of an active ingredient (teverelix) administered to a patient in a single dosage. Said unit dosages is e.g. placed in a suitable syringe in order to provide an easy administration.
• unit dosage provides a final aqueous teverelix-TFA formulation having a molar ratio of teverelix to counter-ion of 1:2.4.
• concentration of teverelix is between 30 mg/ml and 100 mg/ml, and even more preferred between 45 mg/ml and 90 mg/ml, e.g. about 75 mg/ml.
• concentration of teverelix may in some situations be higher than about 100 mg/ml.
• the volume may be between 0.4 ml and 1.6 ml, e.g. about 1.2 ml. Injection given subcutaneous and/or intramuscularly at this concentration and volume, has proven to only provide a mild injection site reaction.
• Example 1 Preparation of teverelix-TFA compositions with different molar ratio
• composition A containing 75 mg teverelix
• 88.28 mg of batch A has to be used, calculated as follows:
• the molar concentration in the 75mg teverelix composition of TFA can be calculated to 0.084 mmol and the molar concentration of teverelix to 0.051 mmol.
• the molar ratio of teverelix to TFA in composition A is 1:1.64.
• composition A In order to prepare a number of different aqueous teverelix-TFA compositions with different molar ratios, twenty-one samples containing 44.14 mg + 5% (41.93 to 46.35 mg) of composition A were accurately weighed in 2 ml glass tubes having a cap through which a reconstitution solution could be added by means of a micropipette.
• TFA solutions containing TFA in 5% mannitol were prepared using a TFA composition obtained from Acros Organics, Geel, Belgium. Said TFA composition were 99 % pure and had a density of 1.535 g/ml. The respective reconstitution solutions are shown in Table 2.
• the respective aqueous teverelix-TFA compositions were prepared by adding 0.5 ml of each of the above reconstitution solutions though the cap of the twenty-one glass tubes containing 44.14 mg + 5% (41.93 to 46.35 mg) of composition A using a micropipette, i.e. three aqueous teverelix-TFA compositions having the same molar ratio were prepared. The mixtures were stirred using a vortex for 1 minute, and the solutions were observed visually for 10 minutes in order to establish if the desired fluid, milky microcrystalline homogeneous aqueous suspension of the teverelix-TFA, were obtained, or if a gel was formed instead.
• Table 3 The results are summarised in Table 3 below:
• microcrystalline content of the aqueous teverelix-TFA compositions in the No. 1 test tubes were further observed under a polarized light microscope supplied by Realux, France.
• a homogeneous suspension of teverelix-TFA was not obtained with a molar ratio at or below 1:2.1, thus it is accordingly preferred that the molar ratio in the aqueous teverelix-TFA suspension is above 1:2.2 and preferably even higher such as at least 1:2.36 ( ⁇ 1:2.4), otherwise said composition cannot be administered via an injection.
• Example 2 Content of soluble teverelix and insoluble teverelix in relation to the molar ratio.
• the No. 2 and No. 3 test tubes for each molar ratio were centrifuged at 10,000 rpm for 10 to 20 minutes, and the concentration of teverelix in the supernatant and pellet were measured using a HPLC analysis.
• a 1% standard solution was prepared by diluting 2 ml of the 100 % standard to 200 ml with the same solvent providing a concentration of 0.001 mg/ml teverelix peptide.
• the pellet obtained after centrifugation was solubilised in water : acetonitrile 65:35 v/v, and the volume was completed to 100 mL with the same solvent. This solution was diluted by 5 (10 mL in 50 mL) and HPLC was performed.
• the degree of insoluble teverelix increases when the amount of trifluoroacetate increases in relation to teverelix, thus at a molar ratio of 1:2.1, about 50 % of the pharmaceutical formulation consist of insoluble teverelix, whereas the amount of insoluble (microcrystalline) teverelix is about 80 % at a molar ratio of 1:2.2. and about 82 % at a molar ratio a molar ratio of 1:2.36 ( ⁇ 1:2.4) in the pharmaceutical formulation.
• Example 3 Plasma concentration In relation to the molar ratio.
• test tubes comprising the aqueous teverelix-TFA compositions shown in table 7 were provided:
• Each rat was injected with 60m1 of the respective solutions using a 25mm 21G luer 6% regular bevel needle (obtainable from Terumo, Leuven, Belgium) and 100(11 luer slip syringe (obtainable from Hamilton Company, Reno, USA) . Plasma concentrations were measured prior to administration, then at lh, 6h, 24h, 48h, 7 days, 10 days,
• the plasma concentration over a four week period was also measured by taking blood samples at regular intervals.
• Example 4 Stability of teverelix in relation to the molar ratio .
• the molar ratio of the starting material was determined using the following calculation:
• teverelix TFA net weight teverelix
• the centrifugation pellet was resuspended with water for injection and made up to 30 mL to form a solution of approximately 10 mg/mL and a molar ratio of approximately
• TFA net weight teverelix
• the solution was made up to 10.0 mL with water for injection to form a solution of teverelix at 10 mg/mL and a molar ratio of 1:2.8 teverelix to TFA.
• TFA net weight teverelix
• teverelix TFA net teverelix
• the centrifugation pellet was resuspended in water for injection (final volume 300mL) to make up a solution of approximately 1 mg/mL and a molar ratio approximately 1:1.7 teverelix to TFA.
• O.OlOg teverelix TFA (net weight teverelix) was reconstituted with 5mL of a 0.001 M trifluoroacetic acid in water for injection in a 10 mL conical flask
• O.OlOg teverelix TFA (net weight teverelix) was reconstituted with 5mL of a 0.0205 M trifluoroacetic acid in water for injection in a 10 mL conical flask
• the stability results are shown in fig. 6 and 7 , and depicts the increase in percentage of impurities during storage according to the molar ratio of the solutions.
• the concentration of teverelix is also relevant for the level of impurities.
• this factor makes the content of acid (trifluoroacetate) in the composition even more important during storage, as a low level of acid will provide a more stable product.
• the molar content of TFA should be at or between 2.2 and 2.8.
• the molar content of TFA at or above 2.2 per mol teverelix are essential for ensuring that the composition/formulation/suspension comprises both soluble and insoluble teverelix, thereby both providing a unique bioavailablity of teverelix, and ensuring that the suspension is easy to administer by subcutaneous and/or intramuscular injection.
• a molar ratio below 1:2.2. will result in undesirable gel-formation, making the suspension very difficult to inject.
• the molar content of TFA at or below 2.8 per mole teverelix is relevant for providing a stable teverelix-TFA product, in which the amount of impurities e.g. undesirable deamidated products, is kept at acceptable levels.
• compositions and formulations provided in the present invention is inexpensive to manufacture, and due to the ease of use they also provides a very simple dosage regime.

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